The competitive grant renewal proposes an integrated program of basic and clinical research to improve the short- and long-term efficacy of allogeneic hematopoietic stem cell transplantation (HSCT). Human candidate diseases for HSCT include patients with acquired (e.g aplastic anemia, autoimmune disease) and genetic (e.g. T-cell deficiency diseases, red blood cell disorders) non-malignant diseases, myelodysplastic syndromes (e.g. T-cell deficiency diseases, red blood cell disorders) non- malignant diseases, myelodysplastic syndromes (MDS), and myeloproliferative disorders. Efforts are focused firstly on the application of non-myeloablative HSCT regimens. The novel aspect of our approach of non-myeloablative HSCT is the use of optimized post-grafting immunosuppression not only to control graft-versus-host disease but also host-versus-graft reactions. This way, the need for toxic pre-transplant therapy has been largely eliminated. Initial emphasis is on HLA-matched related and unrelated transplants. A preclinical canine model focuses on the development of non-myeloablative HSCT strategies for less well matched recipients and on the us of targeted radiation therapy using monoclonal antibodies labeled with alpha-emitting radionuclides. Secondly, for patients with genetic diseases who do not have marrow donors, a project on gene therapy explores optimal gene transfer strategies in a preclinical canine model with ultimate application in human patients with Fanconi anemia. Another laboratory project is aimed at identifying critical cellular components needed to facilitate engraftment in the non-myeloablative setting, particularly when the underlying disease, e.g. MDS, or other conditions, e.g. ABO incompatibilities, pose unique obstacles to this form of therapy. The research studies are supported by five core units which provide sample acquisition and analysis, study design, data processing, statistical analyses, clinical support including that for multi-center studies, long- term follow-up, management of chronic graft-versus-host disease, and grant administration. The principles derived from the proposed studies will make it possible to provide more effective treatment to a greater number of patients.